The alkylthio derivatized DNA and RNA fragments described below will be synthesized and used in collaborative work with Dr. Arnold, Dr. Hughes, and Dr. Parniak to probe the intricate mechanisms of drug inhibition and resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). By crosslinking these fragments to RT, homogeneous populations of key, functionally relevant complexes can be trapped and used for structural and biochemical work. 1. DNA or RNA fragments containing thioalkyl tethers suitable for crosslinking to a protein cysteine residue. The thioalkyl tethers will include both major groove and minor groove sites on the bases or the sugar. The tethers will be introduced either in a post synthetic step using reaction of the appropriate dialkylaminedisulfide with a derivatized base or by incorporation of a phosphoramidite that includes a protected thioalkyl tether. 2. RNA-DNA hybrids containing a specific non-hydrolyzable linkage in the RNA and a thioalkyl tether in the DNA. Non-hydrolyzable linkages, initially a thiophosphate, will be introduced at specific sites during RNA synthesis by incorporation of either a dinucleotide phosphoramidite containing the modified linkage or a modified mononucleotide. 3. Np4N' derivatives containing a thioalkyl tether. The dinucleoside tetraphosphates targeted initially will have a thioalkyl adenosine at one end and 3'-azido-3'deoxythymidine) AZT at the other, and will be prepared by coupling the triphosphate of one with a derivatized monophosphate of the other.